Objective: To determine the pathogenesis of the centrolobular location of liver injury induced by ethanol ingestion. Hypothesis: Ethanol causes centrolobular liver injury by making this location vulnerable to hypoxia. Vulnerability is induced by ethanol through a stimulation of the rate of O2 consumption by the liver. The resultant increase in the rate of O2 extraction from the blood by the liver leaves too little O2 for the centrolobular hepatocytes. Repeated episodes of hypoxia causes centrolobular liver injury in the ethanol fed rats. Eventually the centrolobular lesion called alcoholic hepatitis develops. The latter lesion leads to cirrhosis. Procedures: Rats fed ethanol acutely or chronically and their controls will be subjected to 6 hour bouts of hypoxia through decreased O2 tension. The results will be compared with those of rats fed ethanol and subjected to atmospheric O2 (20%). Centrolobular liver injury will be assessed by measuring calcium, ATP, AMP, ADP, and enzyme content of the centrolobular liver cells to compare with the periportal liver cells which will be relatively spared the centrolobular injury. Electron microscopic assessment of centrolobular liver cell plasma membrane disruption will be done by visualization of a lanthanum leak. Phospholipase hydrolysis of phospholipids will be assessed by measuring changes in phospholipids in the central and periportal liver fractions after hypoxic challenge. The protective effect of catecholamine depletion (reserpine), thyroid hormone depletion (propylthiouracil) and Ca2+ uptake block (chlorpromazine) on these parameters after ethanol pretreatment and hypoxia will be measured using centrolobular and periportal liver fractions.